JOURNAL OF PATEOLOOY.-VO~ XXI. I’LATR XVI

@lia$ Setcbntkoff.

(PLATE XVI.)

BORN MAY 16, 1846-DIED JULY 15, 1916.

ELIAS METCHNIKOFP waa born in the Government of Kharkoff, Ruesia, in 1845, and waa educated at the Univeraity of Kharkoff He early showed a bent towards natural science, and publiebed his first paper at the age of 18. After the completion of his Univereity course he spent four years at various German Universities and at Naplea in zoological study and research especially on marine fauna. Thereafter he held minor appointmenta at Odema and Petrograd, and in 1870 he was appointed Professor of Zoology in the University of the former city-a poeition which he held till 1882. During hie twenty yeam of work as a pure zoologist he was an untiring inveatigator, and upwards of fifty papers came from his pen, dealing largely with the morphology, and especially with the embryology, of invertebrate forma In the early eightiee Metchnikoff developed lesninge towarde pathology, and afbr acting for some years aa Director of the Municipal Bacterio- logical Laboratory in Odessa, he waa invited by Paateur in 1888 to become the head of a department in the newly-founded Pasteur Institute in Paris. Here he spent the rest of his life aa one of the leadera of the brilliant school of workers which during the thirty yeam of ite existence has made the Institute one of the great scientific centres of the world. Though it was to the bacteriologist and the pathologist that his later work chiefly appealed, Metchnikoff himself viewed every subject he investigated from the standpoint of the zoologist. It waa natural, therefore, that, during the past twenty years, when the zoologist and the pathologist have been brought together in the solution of the problema arising from protozoal dimwe, Metchnikoff should play a dominant part aa an adviser and critic of thoee who were bringing to light new and unexpected facts regarding the life hietory of monocellular organisms. He thus also came to be looked on aa one of the foremost protozoologists of hie time.

It is strictly true to srry that in the early eighties the scientific world waa both startled and faacinated by Metchnikoffs promulgation of the view that the essential fact of inflammation was the reaction of the phagocytic cells. To understand the attention which both the theory and ite author attracted it ie well to realise the poaition of

216 OBITUARY;

pathology in 1883. Its chief instrument, the microscope, still lacked its later developments, and microscopic technique could only display the grosser changes in structure produced in diseaea. Thus, though the cellular pathology had been developing for a quarter of a century, the end products of the post-mortem room attracted attention rather than the gradual changes in vital function and structure which led up to them; little was thought of the constant cellular waate of adult life and of the capacities poesessed by the body cells to replace such waste; in spite of Virchow’s insistence on the part played in inflammation by tissue components, the tendency was to look on the proceaa only in its acute vascular manifestations, and the eawntial unity of the acute connective tissue,reaction and of the processes occurring in chronic granulomata was still to be appreciated; the conception of a reaction of living, moving functional cells had scarcely emerged ; the predominance of the bacteria over mechanical and chemical noxa as causes of inflammation in man was not recog- nised, for the success of Listerian surgery still largely rested on an empirical basis. Taking all these considerations into account, it is not surprising that attention should have been ariteted by a theory largely founded on the obeervation of bacterial inflammation, and which aaaigned the dominant part in recovery to the vital capacities of a group of cells whose origin was still obscure and which hitherto had been considered significant chiefly when the failure of their activities resulted in their death.

Metchnikoffs view8 were fouuded on a study of the processes of digestion and of the aequelse of infection in the Protozoa and the avaacular invertebrates, and he traced infection to the fact that an ingested bacterium was to the ingesting cell potential food, even though it might turn out to be capable of multiplying and eventually deetroying its host; digestion and defence were thus in eeeence identical. In the lower Metazoa, though functional differentiation of cells might occur, digestion and defence were still attributes of the aame type of cell. With development of definite germinal layera the mesoderm might exerciee both functions, but later when a specialised mechaniam for secreting enzymes replaced in tracellular digestion this layer retained its defensive powers, and its digestive capacity might be reserved for the removal of useless embryonic structures or dying adult tissuea In animals such as man, with well-developed blood- forming organs and vascular. system, the functions of defence chiefly resided in the leucocytee of the circulating blood, although other cells, notably the endothelia of capillaries and the cella of the type of the larger mononuclear leucocyte found in lymphoid tissue, had similar capacities. Throughout the whole animal aeries Metchnikoff thus found evidence of the existence of active cells capable of moving towards any foreign body introduced into the system, of taking it up if it were a harmless pigment, of encasing i t in plasmodia1 masees if

ELIAS ME TCHNZKOFE 217

i t were insoluble, of englobing it if i t were a noxious bacterium, and either of killing and digesting it or perhaps of being killed in the etruggle. From the observation of the bacterial diaeases of the mammalia he adduced numerous factn to show that phagocytosis of the invading microbes was R constant feature-and, according to his view, the evidence-of a succeesful mistance. Phagocytoeie w a ~ thus the charactenetic fact of inflammation, and wing that it w a ~ recog- nimble before a vaecular ayatem appeared in the animal kingdom, the concurrent changes occurring in veasela when these existed, and to which euch importance had been attached by Cohnheim and others, were to be looked on aa secondary and non-eeeential.

These earlier views of Metchnikoff on inflammation inevitably led him to coneider the reletionship of phegocytoais to immunity. The transition from the idea that the phagocytee p o s d the capacity of selection to the conception of positive and negative chemiotaxie w a ~ an eaey one. The aucceaaful mistance to infection occurred when the phagocytes were atrongly attracted to the invading bacteria, while if the latter repelled the leucocytea death of the host resulted. The development of immunity in au animal consisted in the education of the leucocytea to attack bacteria by which they previouely had been repelled or only weakly attracted. Metchnikoff brought forward numeroue obeervations which he held eupported euch a hypotheeie. He thereby came into eharp conflict with the echool which was rieing at the time-chiefly in Germany-and which b d the explanation of immunity on the changes which occur in the body fluid6 of an animal which haa successfully passed through an attack of infective dieeaee. I n the long controversy which followed the humoraliete, while unable to deny the occurrence of phagocytosis, belittled ita aignificance, while Metchnikoff held to ite being of prime importance. Much of this controversy concerned itaelf with the interpretation to be put on the Pfeiffer reaction, i c . , the bacteriolysis of euch organisme a8 the cholera vibrio in the peritoneal cavity of immunised animals. Metchnikoff put forward observation6 to show that the presence of phagocytes and the Occurrence of phagolyms w a ~ essential to the development of the reaction, that it did not take place in body fluids poor in phsgocytm or inacceseible to them, euch 88 the eubcutaneous lymph or the aqueoua humour. He stated that even in the peritoneal cavity if phagocytoeie were inhibited by injecting bouillon previous to the introduction of the bacteria, the Pfeiffer phenomenon could not be olicited. while at the name time a highly active phapytosie could be obeerved. He further pointed out that in certain infectiona, notably by the anthrax bacillue and the pyogenic cocci, not only did the Pfeiffer phenomenon not occur but, unlike the cl~ee of immunktion again& the cholera vibrio, the serum of a vaccinated animal could not be UBed for the paesive protection of a fresh animal. In theee a888 an increesed phagocytic activity of specially the polymorph leuco-

21 8 OBITUAR I?

cytes was the sole indication of immunity. How comes it then that under certain circumstances such undoubted changes in the properti- of the blood Berum accompany immunieation ? According b Metchnikoffs view the properties of the serum do not completely or indeed accurately represent those of the blood as it circulates in an animal's body. By experiments in which coagulation W R ~ prevented by receiving blood in paraftined tubes he sought to prove that the plasma contains none of the thermolabile bodiea whose action, from the humomlist standpoint, forms such an important element in the bactericidal quality of the serum. These bodiee originate in the phagocytes and are ementially part of the mechanism by which them phsgocytee diapow intracellularly of their prey; they only become free in body fluids either by being secreted from their parent cells or as the result of a disintegration of these cells, such as accompanies intracorporeal phagolyks or extracorporeal blood coagulation. Metch- nikoff denominated them cytaaea, and attributed to them the leading r6le in the effectivenw of the phagocytosis on which, according to him, natural immunity depends. Towards the therniostable fixateurs he took rather a different attitude. While not dogmatising, he considered it probable that these also had a pbagocytic origin, founding his view on the fact that when phagocytosis of goose red corpuscles in the guinea-pig is slight the yield of immune body is correspondingly amall. He admitted, however, that, wherever they be formed, fixateurs escape in vivo into the body fluids, for he found that the addition of corn- plement to the subcutaneous lymph of an animal immuniaed against the cholers vibrio enabled the PfeSer phenomenon to be elicited in the mixture. The function of the fixateurs was to prepare bacteria for the action of the complement. It waa thus that Metchnikoff fitted his views on the dominant importance of phagocytosis to those generally accepted regarding the properties of the sera. About the beginning of the present century the acute phase of the controversy between the cellular and the humoral schools died down, largely because neither side could devise crucial experiments capable of settling the outstanding points of dispute. It might have been expected that the discovery of the opeonic properties of the serum by Wright would reopen the question of the significance of phagocytosis, but this has not been the case, and up to the preaeut day the cellular school has not been able to satisfactorily prove that phsgocytosis is an easential factor in immunity, and, on the other hand, the humoraliste have given little attention to the origin of the new capacities which appear in the serum of an immunieed animal and of their idation to the living protoplasm of the body. While, therefore, it cannot be maintained that Metchnikoff conclusively proved his fundamental thesis, his work h a been of the higheat value to pathology. It gave a fresh aapect to the consideration of the manifold phenomena observed in inflammation. It did away with the idea that the causal noxa

ELZAS ME TCHNlKOF%: 219

produced au effect on this or that tissue element to which were trace- able all the aubeequent phenomena of the proceas in seriea It aub- stituted the view that on each .of the different elements in the inflamed apes the noxa haa a direct and it may be a specific influence. Thia led to the clear differentiation of the necrotic or necrobiotic effects of the noxa from those which constitute the reaction, and, moat important of all, by focnesing attention on the latter, aa exhibit- ing bodily powers a t work, it laid the foundation of the pathology of function.

Turning aside from the general problems of infection, Metchnikoff in the early years of the present century devoted himself to the particular problem of syphilie, which waa still an obscure one. While the diaease w a recogniaed a~ undoubtedly infectious, little had up till then been done to study the infection under experiniental conditions. Realiaing that. from their zoological relationship to man, the higher apes were likely to show susceptibility to the d i m , Metchnikoff used t h m animala for his experimenta With material derived from the disease in man he e~coeeded in originating in them not only primary 8orea but papular skin eruptions and condylomata such 8s are oharacteristic of the human dieease. While the investigation waa still proceeding, Schaudinn’e dimvery of the Spirochcete p a U i d a wa8 anuounced, and Metchnikoff found tbe organism in hie experimental leaions. He furtber demonstrated the fact that the infection could -he transferred by passage from ape to ape, and in etudying experimental leeiona in the lower monkeys he advanced the view that while in some speciea ( M i u s sink@, M a c a ~ c s rhslu) p u v q e attenuated the human virus for the chimpanzee, in other cawa (Macacua cynomolgu) no such attenuation occurred. The demonstration by Metchnikoff of the possibility of infecting the lower animals with syphilis did much to facilitate the obtaining of the later reaulta which have elucidated so many of the puzzling questions regarding the pathology of the diaease which were formerly unanswerable.

During the last ten years of his life Metchnikoffs mind waa most occupied with the problem of inteetinal intoxication. He started from the view that a capacious large ink t ine in man wm an inheritance of an organ weful in the wild life of the higher mmmalia from which man is descended. Seeing that it no longer performed a digeetive function, and that ita poeseeeion as a reservoir was no longer 8

neceeeity, Metchnikoff held that i t waa now an actual danger in that it could be the site for the multiplication of bacteria, the absorption of whose producta might be harmful to the body aa a whola He found confirmation of his viewe in a minute study of a fruit-eating bat poseeaaing a rudimentary large inteatine which ie almoet entirely free from hcteria Developing his ideas, he looked on the B. perfringma group of bacteria with their proteolytic capacities 88 the dangerous cams of inteetinal intoxication, and held that they acted

220 ELZAS METCHNZKOF'

by producing substances of the aromatic series such aa indol and skatol which the body could only partly combat by converting them into leee toxic sulphoconjugate bodies. While these products originate acutely toxic symptom in animals, he considered he had obtained evidence that in small quantities they were capable of originating the interstitial changes in vital organs which are so commonly associated with fatal disease. His attempt to combat intestinal putrefaction by the use of sour-milk products 80 commonly used by primitive and, according to Metchnikoff, long-lived races appealed to the popular fancy. The observations on which he baaed this treatment are no doubt capable of interpretations other than Metchnikoff drew from them, but they might with advantage be further elaborated. The study of the processes by which life might be prematurely terminated was miugled in Metchnikofs mind with that of the phenomena of old age and of natural death. His views on this subject were largely speculative, and led him into fields of thought which his habit of mind and his training rendered him unfitted to traverse. But even though from his philoeophical standpoint it leads nowhere, the scientific consideration of the phenomena which culminate in death is a necessary completion of the study of the living organism, and thus interest attaches to Metchnikoffs observations on the part taken by phagocytes in the senility of such cells as these of the hair and the brain, and to his laat published paper on the auto-intoxication which terminates the bacterium-free life of the silk-worm moth.

There is little doubt that Metchnikoffs fame will rest on his work on the phagocytosis of bacteria. Whatever significance may ultimately attach to the capacities of bodily cells to take up foreign matter, whether inorganic or organic, and to dispose of the decaying cells of the organism to which they belong, the worker who first developed a knowledge of the fundamental data must inevitably occupy a foremost place. Much of the controversy on the subject which a t the time clogged the feet of progress is traceable to the fact that in their earlier papers both Metchnikoff and his critics had committed themselves to positions which later discoveries rendered untenable. Truths were established by both parties to the debate, and thew are available as a starting-point to a fresh generation of workers not committed to either side.

Apart from his personal contributions to knowledge Metchnikoff attracted to himself a school of devoted pupils who have made their mark in protozoology and bacteriology. These have given generous expreesion to the help and stimulus they received from him, and all who are familiar with the work which has been issued from the Pasteur Institute of Paris know how wide and important Metchnikofs influence haa been.

JAMES RITCHIK